Although late-life depression (LLD) is a significant cause of distress and disability, its pathophysiology remains poorly understood. This application for a Mentored Patient-Oriented Research Career Development Award proposes a four year training plan and mentored research project that will prepare the applicant to become an independent investigator of the biology and treatment of late-life mood disorders. The training plan includes (1) completion of a Masters of Science in Clinical Research, (2) courses in neuroanatomy, systems neuroscience and neuroimaging, (3) hands-on tutorials in biomedical imaging and data analyses and (4) mentoring in the neuroimaging, biology and treatment of late-life mood disorders. The mentored research project includes an integrated, multimodal magnetic resonance imaging (MRI) study of late-life depression (LLD). One theory of the etiology of LLD proposes that ischemic white matter disruption results in depression by disconnecting critical cortical-subcortical nodes within a mood regulation neural network. Thus, structural and functional abnormalities associated with LLD should be anatomically correlated. To test this, 40 subjects (>60 years) with late-life depression (onset after 50 years of age) and 40 non-depressed matched controls will undergo 1 hour MR imaging to include: (1) high-resolution structural imaging, (2) diffusion tensor imaging (DTI) and (3) functional MRI (fMRI) during two tasks: the Counting Stroop and the Emotional Counting Stroop. Frontal lobe white matter integrity and functional brain acitivity during fMRI tasks will be compared between groups and the correlation of structural and functional findings will be calculated. Using DTI tractography, tracts connected to brain regions involved in cognitive and cognitive-emotional processing will be identified and differences in white matter integrity in these tracts will be correlated with differences in brain activation during fMRI tasks. The applicant will receive training in other structural imaging methods, including voxel-based morphometry and magnetization transfer imaging. These findings will test the theory that white matter disease can result in LLD by disrupting connections between components of a brain network critical to normal mood regulation and provide groundwork for future structurally and functionally integrated imaging studies of late-life depression. It is hoped that a better understanding of the pathophysiology of late-life depression will lead to improvements in its diagnosis, prevention and treatment.